Britta Siegmund

Charité Universitätsmedizin Berlin, Berlín, Berlin, Germany

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Publications (145)605.78 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Thiopurines (azathioprine and 6-mercaptopurine) are the most frequently used drugs in the treatment of patients with Crohn's disease. In current guidelines published by the German Society of Gastroenterology, Nutritional and Metabolic Diseases (DGVS) in 2014 and by the European Crohn´s and Colitis Organisation (ECCO) in 2010 different indications have been suggested. However, efficacy of azathioprine has been substantially questioned by recent publications in adults as well as in children examining the efficacy of early initiation of this treatment. These articles were published after release of the aforementioned guidelines. Therefore, in this survey recently published data are discussed on the background of our knowledge on the efficacy of azathioprine and 6-mercaptopurine developed in many years, and suggestions for the future use of these substances in the treatment of patients with Crohn's disease will be provided. © Georg Thieme Verlag KG Stuttgart · New York.
    Zeitschrift für Gastroenterologie. 12/2014; 52(12):1423-30.
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    Zeitschrift für Gastroenterologie. 12/2014; 52(12):1431-84.
  • LeaI Kredel, Arvind Batra, Britta Siegmund
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    ABSTRACT: This review summarizes current knowledge on the contribution of mesenteric adipose tissue in intestinal inflammation. We will describe the cellular and humoral characteristics of creeping fat, their potential impact for Crohn's disease and propose a working model for the critical interplay between the creeping fat and the inflamed intestine.
    Current opinion in gastroenterology. 09/2014;
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    ABSTRACT: Early enteral nutrition is recommended for patients in intensive care units, but nutrition provision is often hindered by a variety of unit-specific problems.
    American journal of critical care : an official publication, American Association of Critical-Care Nurses. 09/2014; 23(5):396-403.
  • J Maul, B Siegmund
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    ABSTRACT: Chronic inflammatory bowel diseases are mainly represented by Crohn's disease and ulcerative colitis. Current epidemiological data indicate a rise in incidence over the last five decades in the Western world. Consequently resulting not only in the reconsideration of the pathogenesis of inflammatory bowel diseases but furthermore emphasizing the need for a curative approach. With this review we aim to provide a concise overview on pathogenesis, diagnostics as well as therapy with a particular focus on medical strategies after ileocecal resection in Crohn's disease. In the end the near future with regard to therapeutic strategies to be introduced into daily clinical work will be described.
    Deutsche medizinische Wochenschrift (1946). 09/2014; 139(36):1771-1775.
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    ABSTRACT: Histomorphology remains a powerful routine evaluating intestinal inflammation in animal models. Emphasizing the focus of a given animal study, histopathology can overstate differences between established models. We aimed to systematize histopathological evaluation of intestinal inflammation in mouse models facilitating interstudy comparisons. Samples of all parts of the intestinal tract from well-established mouse models of intestinal inflammation were evaluated from hematoxylin/eosin-stained sections and specific observations confirmed by subsequent immunohistochemistry. Three main categories sufficiently reflected the severity of histopathology independent of the localization and the overall extent of an inflammation: (i) quality and dimension of inflammatory cell infiltrates, (ii) epithelial changes and (iii) overall mucosal architecture. Scoring schemata were defined along specified criteria for each of the three categories. The direction of the initial hit proved crucial for the comparability of histological changes. Chemical noxes, infection with intestinal parasites or other models where the barrier was disturbed from outside, the luminal side, showed high levels of similarity and distinct differences to changes in the intestinal balance resulting from inside events like altered cytokine responses or disruption of the immune cell homeostasis. With a high degree of generalisation and maximum scores from 4-8 suitable scoring schemata accounted specific histopathological hallmarks. Truly integrating demands and experiences of gastroenterologists, mouse researchers, microbiologists and pathologists we provide an easy-to-use guideline evaluating histomorphology in mouse models of intestinal inflammation. Standard criteria and definitions facilitate classification and rating of new relevant models, allow comparison in animal studies and transfer of functional findings to comparable histopathologies in human disease.
    International journal of clinical and experimental pathology 08/2014; 7(8):4557-4576. · 2.24 Impact Factor
  • Lea-Maxie Haag, Britta Siegmund
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    ABSTRACT: Inflammatory bowel diseases (IBD) with its two major forms Crohn’s disease (CD) and ulcerative colitis (UC) are chronic relapsing disorders leading to inflammation of the gastrointestinal tract. Although the precise aetiology of IBD remains unclear, several factors are believed to contribute to disease pathogenesis. Among these, the role of the intestinal microbiota has become more and more appreciated. Evidence from experimental and clinical studies strongly suggests that chronic intestinal inflammation results from a dysregulated immune response towards components of the microbiota in genetically susceptible hosts. The growing perception of the microbiota as a major driver of disease pathogenesis raises the question, if the intestinal microbiota can be used as a therapeutic target in CD. Based on what we know about host microbiota interactions in health and disease, the objective of this review is to address the question if the microbiota holds the key to the future therapy in CD.
    Baillière&#x027 s Best Practice and Research in Clinical Gastroenterology 06/2014; · 3.16 Impact Factor
  • B Siegmund
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    ABSTRACT: The challenge of the mucosal immune system is to develop tolerance toward intestinal antigens. Considering the quantity of bacteria that continuously attack the intestinal barrier, one can only imagine the complexity involved. To master this task, a tight network between the intestinal microbiota, the barrier, immune cells of the lamina propria as well as the adjacent mesenteric fat tissue is required. The key pathways involved have been revealed by the genome-wide association studies as well as functional data from experimental models. However, although knowledge with regard to the pathogenesis of chronic inflammatory bowel disease has been increasing continuously over recent decades, the current therapeutic strategies are limited to controlling the pro-inflammatory effector phase rather than achieving cure. The best example is cytokine neutralizing antibodies. The present review aims to describe the role of the various cell populations within the intestinal wall for disease pathogenesis and, thus, identify possible therapeutic strategies.
    Der Internist 05/2014; · 0.33 Impact Factor
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    ABSTRACT: Severe courses of Crohn's disease (CD) during pregnancy are rare. However, if occurring, the risk of miscarriage and low birth weight is increased. At present, only limited data is available on the treatment of CD during pregnancy. In particular, there are no standard guidelines for surgical therapy. Nevertheless, surgery is often unavoidable if complications during the course of the disease arise. This study provides a critical overview of conventional and interventional treatment options for CD complications during pregnancy and analyses the surgical experience gained thus far. For illustrative purposes, clinical cases of three young women with a severe clinical course during pregnancy are presented. After treatment-refractory for conservative and interventional measures, surgery remained as the only treatment option. In all cases, a split stoma was created after resection to avoid anastomotic leaks that would endanger the lives of mother and child. The postoperative course of all three patients was uneventful, and pregnancy remained intact until delivery. No further CD specific medication was required before birth. The management of CD patients during pregnancy requires close interdisciplinary co-operation between gastroenterologists, obstetricians, anaesthetists and visceral surgeons. For the protection of mother and child treatment should thus be delivered in a specialised centre. This article demonstrates the advantages of surgical therapy by focusing on alleviating CD complaints and preventing postoperative complications.
    International Journal of Colorectal Disease 05/2014; · 2.24 Impact Factor
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    ABSTRACT: α-Haemolysin (HlyA) influences host cell ionic homeostasis and causes concentration-dependent cell lysis. As a consequence, HlyA-producing Escherichia coli is capable of inducing 'focal leaks' in colon epithelia, through which bacteria and antigens translocate. This study addressed the role of HlyA as a virulence factor in the pathogenesis of colitis according to the 'leaky gut' concept. To study the action of HlyA in the colon, we performed oral administration of HlyA-expressing E coli-536 and its isogenic α-haemolysin-deficient mutant (HDM) in three mouse models: wild type, interleukin-10 knockout mice (IL-10(-/-)) and monoassociated mice. Electrophysiological properties of the colonised colon were characterised in Ussing experiments. Inflammation scores were evaluated and focal leaks in the colon were assessed by confocal laser-scanning microscopy. HlyA quantity in human colon biopsies was measured by quantitative PCR. All three experimental mouse models infected with HlyA-producing E coli-536 showed an increase in focal leak area compared with HDM. This was associated with a decrease in transepithelial electrical resistance and an increase in macromolecule uptake. As a consequence, inflammatory activity index was increased to a higher degree in inflammation-prone mice. Mucosal samples from human colon were E coli HlyA-positive in 19 of 22 patients with ulcerative colitis, 9 of 9 patients with Crohn's disease and 9 of 12 healthy controls. Moreover, focal leaks were found together with 10-fold increased levels of HlyA in active ulcerative colitis. E coli HlyA impairs intestinal barrier function via focal leak induction in the epithelium, thereby intensifying antigen uptake and triggering intestinal inflammation in vulnerable mouse models. Therefore, HlyA-expressing E coli strains should be considered as potential cofactors in the pathogenesis of intestinal inflammation.
    Gut 02/2014; · 10.73 Impact Factor
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    ABSTRACT: Histone deacetylase (HDAC) inhibitors have primarily been associated with an anti-proliferative effect in vitro and in vivo. Recent data provide evidence for an anti-inflammatory potency of HDAC inhibitors in models of experimental colitis. As the balance of T cell subpopulations is critical for the balance of the mucosal immune system, this study explores the regulatory potency of HDAC inhibitors on T cell polarization as a mechanistic explanation for the anti-inflammatory effects observed. While HDAC inhibition suppressed the polarization towards the pro-inflammatory T helper 17 (Th17) cells, it enhanced forkhead box P3 (FoxP3)+ regulatory T cell polarization in vitro and in vivo at the site of inflammation in the lamina propria. This was paralleled by a down-regulation of the IL-6 receptor (IL 6R) on naive CD4+ T cells on the mRNA as well as on the protein level, and changes in the chromatin acetylation at the IL6R gene and its promoter. Downstream of the IL-6R, HDAC inhibition was followed by a decrease in signal transducer and activation of transcription 3 (STAT3) phosphorylation as well as RAR-related orphan receptor T (RORγT) expression, thus identifying the IL 6/STAT3/IL-17 pathway as an important target of HDAC inhibitors. These results directly translated to experimental colitis, where the IL-6R expression was suppressed in naive T cells, paralleled by a significant reduction of Th17 cells in the lamina propria of ITF2357-treated animals resulting in amelioration of disease. The present study indicates that in experimental colitis inhibition of HDAC exerts an anti-inflammatory potency by directing T helper cell polarization via targeting the IL-6 pathway.
    Journal of Biological Chemistry 01/2014; · 4.65 Impact Factor
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    Tassilo Kruis, Arvind Batra, Britta Siegmund
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    ABSTRACT: Over the last decade it became broadly recognized that adipokines and thus the fat tissue compartment exert a regulatory function on the immune system. Our own group described the pro-inflammatory function of the adipokine leptin within intestinal inflammation in a variety of animal models. Following-up on this initial work, the aim was to reveal stimuli and mechanisms involved in the activation of the fat tissue compartment and the subsequent release of adipokines and other mediators paralleled by the infiltration of immune cells. This review will summarize the current literature on the possible role of the mesenteric fat tissue in intestinal inflammation with a focus on Crohn's disease (CD). CD is of particular interest in this context since the transmural intestinal inflammation has been associated with a characteristic hypertrophy of the mesenteric fat, a phenomenon called "creeping fat." The review will address three consecutive questions: (i) What is inducing adipocyte activation, (ii) which factors are released after activation and what are the consequences for the local fat tissue compartment and infiltrating cells; (iii) do the answers generated before allow for an explanation of the role of the mesenteric fat tissue within intestinal inflammation? With this review we will provide a working model indicating a close interaction in between bacterial translocation, activation of the adipocytes, and subsequent direction of the infiltrating immune cells. In summary, the models system mesenteric fat indicates a unique way how adipocytes can directly interact with the immune system.
    Frontiers in Immunology 01/2014; 4:510.
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    Lea I Kredel, Britta Siegmund
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    ABSTRACT: Obesity has become one of the main threats to health worldwide and therefore gained increasing clinical and economic significance as well as scientific attention. General adipose-tissue accumulation in obesity is associated with systemically increased pro-inflammatory mediators and humoral and cellular changes within this compartment. These adipose-tissue changes and their systemic consequences led to the concept of obesity as a chronic inflammatory state. A pathognomonic feature of Crohn's disease (CD) is creeping fat (CF), a locally restricted hyperplasia of the mesenteric fat adjacent to the inflamed segments of the intestine. The precise role of this adipose-tissue and its mediators remains controversial, and ongoing work will have to define whether this compartment is protecting from or contributing to disease activity. This review aims to outline specific cellular changes within the adipose-tissue, occurring in either obesity or CF. Hence the potential impact of adipocytes and resident immune cells from the innate and adaptive immune system will be discussed for both diseases. The second part focuses on the impact of generalized adipose-tissue accumulation in obesity, respectively on the locally restricted form in CD, on intestinal inflammation and on the closely related integrity of the mucosal barrier.
    Frontiers in Immunology 01/2014; 5:462.
  • Dr. J. Maul, B. Siegmund
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    ABSTRACT: Bei einem Großteil der Patienten mit einem Morbus Crohn wird im Krankheitsverlauf die Indikation zu einer Darmresektion gestellt. Für den Gastroenterologen stellt sich postoperativ die Frage der Nachsorge bzw. der Einleitung einer immunsuppressiven Therapie. Mit der vorliegenden Übersicht soll basierend auf den aktuellen Leitlinien ein Vorgehen für die klinische Praxis dargestellt werden. Risikofaktoren für ein postoperatives Rezidiv sind Rauchen, frühere intestinale Operationen, penetrierende oder perianale Erkrankung sowie ausgedehnte Dünndarmresektionen. Gleichermaßen ist das Rezidivrisiko bei Vorliegen von Zeichen der Entzündung im Bereich der Anastomose deutlich erhöht (mehr als 5 Aphthen, Rutgeerts-Score ≥ i2). Liegen keine Risikofaktoren vor, so wird daher die Durchführung einer endoskopischen Evaluation der Anastomose 6–12 Monate postoperativ empfohlen. Bei Niedrigrisikopatienten kann eine Mesalazinprophylaxe durchgeführt werden. Bei Patienten mit mehreren Risikofaktoren oder entzündlichen Veränderungen an der Anastomose sollte eine Prophylaxe mit Azathioprin oder eine Therapie mit einem TNF-α-Antikörper in Abhängigkeit vom Therapieansprechen in der Anamnese begonnen werden. Ziel aktueller Untersuchungen ist es, das Rezidivrisiko basierend auf Risikofaktoren oder endoskopischen Entzündungszeichen sowie den Nutzen einer medikamentösen Rezidivprophylaxe besser zu definieren.
    Der Gastroenterologe 01/2014; 8(3).
  • Gut 07/2013; · 10.73 Impact Factor
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    ABSTRACT: The coloproctomucosectomy (CPM) is the procedure of the choice for the surgical treatment of ulcerative colitis (UC). In cases with pronounced immunosuppression (IS), a 3-step (3S) procedure [i.e., subtotal colectomy and ileal pouch-anal anastomosis (IPAA) and finally ileostomy reconstruction] is often selected. Fewer perioperative complications can be expected compared to the 2-step (2S) procedure; however, an additional in-hospital stay and surgical intervention are necessary. The aim of the present study was to compare both approaches using the clinical outcome of our patients undergoing IPAA to determine efficacy of these two concepts. From 1997-2010, a total of 225 patients were operated using a 2S or 3S IPAA procedure. Clinical outcomes were evaluated based on the number of surgical steps for the ileoanal pouch procedure and IPAA. The survey was performed within the scope of prospective study. Of the 225 patients with CPM, 66 were excluded due to a diagnosis other than UC (familial adenomatous polyposis, indeterminate colitis, Crohn's disease) and patients with permanent ILS procedures without the possibility or wish for an IPAA (n = 54). Included were 71 patients with 2S (w = 30, m = 41) and 34 patients with 3S procedures (w = 21, m = 13). Compared to the 2S procedure, the 3S procedure was shown to have shorter operation times (246 versus 296 min; p = 0.05), shorter hospital stays (15.5 versus 24.6 days; p = 0.05), shorter intensive care unit stays (3.3 versus 7.2 days; p = 0.05), and fewer major complications (5.9 % versus 22.5 %; p = 0.035). Patients with 3S procedures had a higher BMI (26.2 versus 23.1 kg/m²; p = 0.05) and fewer required IS (10 % vs. 62 %; p < 0.05). The decision for a 3S procedure in UC and pronounced IS is advisable and justified. Using a 3S procedure, immunosuppression and its influence on perioperative morbidity are thus reduced. The IPAA can be performed with shorter operation times, shorter hospital stays and fewer major complications.
    Der Chirurg 06/2013; · 0.52 Impact Factor
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    ABSTRACT: BACKGROUND: Acute pancreatitis is the most common complication of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). In spite of continuing research, no pharmacologic agent capable of effectively reducing the incidence of ERCP-induced pancreatitis has found its way into clinical practise. A number of experimental studies suggest that intrapancreatic calcium concentrations play an important role in the initiation of intracellular protease activation, an initiating step in the course of acute pancreatitis. Magnesium can act as a calcium-antagonist and counteracts effects in calcium signalling. It can thereby attenuate the intracellular activation of proteolytic digestive enzymes in the pancreas and reduces the severity of experimental pancreatitis when administered either intravenously or as a food supplement. METHODS: We designed a randomized, double-blind, placebo-controlled phase III study to test whether the administration of intravenous magnesium sulphate before and after ERCP reduces the incidence and the severity of post-ERCP pancreatitis. A total of 502 adult patients with a medical indication for ERCP are to be randomized to receive either 4930 mg magnesium sulphate (= 20 mmol magnesium) or placebo 60 min before and 6 hours after ERCP. The incidence of clinical post-ERCP pancreatitis, hyperlipasemia, pain levels, use of analgetics and length of hospital stay will be evaluated. CONCLUSIONS: If magnesium sulphate is found to be effective in preventing post-ERCP pancreatitis, this inexpensive agent with limited adverse effects could be used as a routine pharmacological prophylaxis.Trial registration: Current Controlled Trials ISRCTN46556454.
    BMC Gastroenterology 01/2013; 13(1):11. · 2.11 Impact Factor
  • Donata Lissner, Britta Siegmund
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    ABSTRACT: Since the incidence of inflammatory bowel diseases including ulcerative colitis is continuously increasing worldwide, there is a strong need for effective treatment strategies. However, there is no therapy allowing for healing ulcerative colitis; consequently, the available medications will have to be applied at their best. The preferred option for mild pan- or left-sided colitis is still mesalazine. One can only emphasize that the formulations allowing for once daily dosing are not only equally effective, but even facilitate the implication of long-term therapy in daily life. In case steroids are frequently required to control disease, further immunosuppressive therapy should be introduced in order to minimize steroid exposure. Thiopurines represent the first-choice immunosuppressive medication. In more severe cases, early escalation to combinatory therapies with anti-TNF antibodies should be considered with the possibility of therapy deescalation after induction of remission. Major difficulties arise with steroid-refractory acute flares. Here cyclosporine as well as anti-TNF strategies can be initiated. However, in case of severe disease, the high 1-year colectomy rate of about 50% should be considered. If short-term surgery is an option due to disease severity, cyclosporine might be advantageous since the half-life is short compared to infliximab or adalimumab. The central problem of all therapeutic approaches is that because we chase after the disease, solid markers that allow for prediction of the future disease course are desirable. In fact, the CD8+ transcriptome might fill this gap and will potentially lead to the classification of patients in low- and high-risk groups.
    Digestive Diseases 01/2013; 31(1):91-94. · 2.73 Impact Factor
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    ABSTRACT: The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model. The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression. Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. stimulated splenocytes after treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment . These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.
    PLoS ONE 01/2013; 8(2):e56867. · 3.53 Impact Factor
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    ABSTRACT: Forkhead box P3 positive (Foxp3(+)) regulatory T (Treg) cells suppress immune responses and regulate peripheral tolerance. Here we show that the atypical inhibitor of NFκB (IκB) IκB(NS) drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, IκB(NS) deficiency leads to a substantial reduction of Foxp3(+) Treg cells in vivo and impaired Foxp3 induction upon transforming growth factor-β (TGF-β) treatment in vitro. Moreover, fewer Foxp3(+) Treg cells developed from IκB(NS)-deficient CD25(-)CD4(+) T cells adoptively transferred into immunodeficient recipients. Importantly, IκB(NS) was required for the transition of immature GITR(+)CD25(+)Foxp3(-) thymic Treg cell precursors into Foxp3(+) cells. In contrast to mice lacking c-Rel or Carma1, IκB(NS)-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IκB(NS) critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IκB(NS) could modulate the Treg cell compartment.
    Immunity 11/2012; · 19.80 Impact Factor

Publication Stats

3k Citations
605.78 Total Impact Points

Institutions

  • 2004–2014
    • Charité Universitätsmedizin Berlin
      • • Department of Gastroenterology, Infectiology and Rheumatology
      • • Institute of Health Sciences Education and Nursing Science
      • • Institute of Medical Informatics
      Berlín, Berlin, Germany
    • Mental Health Center of Denver
      Denver, Colorado, United States
  • 2013
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 2008
    • St. Marien- und St. Annastiftskrankenhaus
      Ludwigshafen, Rheinland-Pfalz, Germany
    • University of Illinois at Chicago
      • Department of Kinesiology and Nutrition
      Chicago, IL, United States
  • 2001–2006
    • University of Colorado
      • Department of Medicine
      Denver, CO, United States
  • 2005
    • University Hospital of Lausanne
      • Institut universitaire de pathologie
      Lausanne, VD, Switzerland
  • 2003
    • Freie Universität Berlin
      Berlín, Berlin, Germany
  • 1997–2001
    • Ludwig-Maximilian-University of Munich
      • • Department of Clinical Pharmacology
      • • Department of Internal Medicine II
      München, Bavaria, Germany